Trypanocidal activity of new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine derivatives: Synthesis, in vitro and in vivo studies
Graphical abstract
Introduction
Chagas disease remains a neglected tropical disease, although it was discovered more than 100 years ago by Carlos Chagas.1 The protozoan Trypanosoma cruzi was described as the causative agent in 1909,2 which can be transmitted by triatomine insects. The mechanisms of transmission include vectorial transmission, oral, congenital, blood transfusion and organ transplantation.3 Chagas disease can develop into three clinical phases: the acute, indeterminate, and chronic phase. If untreated, the acute phase can develop into a chronic phase.1 The rate of cases that evolve to the chronic symptomatic phase is around 30%.4 Symptomatic patients may usually present morphological and functional changes in organs such as the heart, the colon and the esophagus. The treatment available is based on nitroheterocyclic molecules, Benznidazole and Nifurtimox, which are mainly used to treat patients during the acute phase of the disease as they have little effectiveness in adults with late chronic disease.1
The 1H-pyrazolo[3,4-b]pyridine is one of the potential heterocyclic rings that have been showing wide promising biological applications.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 In our previous work, we developed 4-(benzylidene-carbohydrazide)-1,6-diphenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine compounds for trypanocidal activity. The N′-(4-hydroxybenzylidene)carbohydrazide derivative (1, Fig. 1) showed in vitro activity against both trypomastigote and amastigote forms of T. cruzi comparable to the benznidazole drug, and a lower cell toxicity profile in mammalian cells.16
Based on the promising biological profile of the hit compound 1, herein, we synthesized new 1,6-diphenyl-1H-pirazolo[3,4-b]pyridine compounds structurally related to 1 and evaluated their trypanocidal activity and cytotoxicity profile.
Section snippets
Chemistry
The reactions were monitored by TLC performed on aluminum sheets precoated with silica gel 60 (HF-254, Merck) to a thickness of 0.25 mm and the chromatograms were viewed under ultraviolet light (254–365 mm). The ultrasound assisted reactions were carried out on an ultrasonic bath Unique UltraCleaner, model 1600 A, at 40 KHz and ultrasonic potency of 135 W. Melting points were determined in a capillary of a Thomas Hoover PC03296 apparatus and are given uncorrected. IR spectra were recorded on a
Synthesis
The new compounds were planned exploring the hydroxyl group in different positions of the benzylidene moiety as well as it’s O-acetyl form, and the bioisosteric concept between carbohydrazide and 2,3-dihydro-1,3,4-oxadiazole moieties.27, 28, 29 In order to investigate the influence of the position of the hydroxyl group at the benzilidene moiety on the trypanocidal activity, we have synthesized four new hydroxybenzilidene-carbohydrazide analogs of 1 (2a-d). We have also synthesized seven new
Conclusions
We synthesized 11 new 1,6-diphenyl-1H-pirazolo[3,4-b]pyridine compounds structurally related to N′-(4-hydroxybenzylidene)carbohydrazide derivative from previous works. The use of glycerol as a reaction medium to produce N′-benzylidene-carbohydrazides (1, 2a-d) proved to be more advantageous than the conventional medium. All compounds tested showed some level of trypanocidal activity in vitro. The comparison between the positions of the substituent group on the phenyl ring indicated that the
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors would like thank for the support of the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-BR) for the JLSR and JCVS fellowships (finance code 001), and the Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) [E-26/200.930/2017].
The authors would also like to thank the Laboratório Multiusuário de RMN de Líquidos (LABRMN-L) of the Chemistry Institute of UFRJ for its support in the generation of 400 MHz NMR spectra.
References (44)
- et al.
Chagas disease
Lancet
(2018) - et al.
Trypanosoma cruzi immunoproteome: Calpain-like CAP5.5 differentially detected throughout distinct stages of human Chagas disease cardiomyopathy
J Proteomics
(2019) - et al.
Synthesis and analgesic properties of 5-acyl-arylhydrazone-1H-pyrazolo[3,4-b]pyridine derivatives
Pharm Acta Helv
(1994) - et al.
Synthesis, in vitro evaluation, and SAR studies of a potential antichagasic 1H-pyrazolo[3,4-b]pyridine series
Bioorg Med Chem
(2007) - et al.
Development of practical syntheses of potent non-nucleoside reverse transcriptase inhibitors
Tetrahedron
(2009) - et al.
Synthesis and mechanistic evaluation of novel N’-benzylidene-carbohydrazide-1H-pyrazolo[3,4-b]pyridine derivatives as non-anionic antiplatelet agents
Eur J Med Chem
(2017) Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays
J Immunol Methods
(1983)- et al.
1,3,4-Oxadiazoles: An emerging scaffold to target growth factors, enzymes and kinases as anticancer agents
Eur J Med Chem
(2015) - et al.
NMR study of conformation and isomerization of aryl- and heteroarylaldehyde 4-tert-butylphenoxyacetylhydrazones
J Mol Struct
(2006) - et al.
Current drug therapy and pharmaceutical challenges for Chagas disease
Acta Trop
(2016)